Lung cancer is the leading cause of cancer-related mortality nationwide. In patients with metastatic non-small cell lung cancer, recent randomized trials have demonstrated superior efficacy of combined chemotherapy and T cell checkpoint blockade over conventional treatment. These studies have made combination chemotherapy and T cell checkpoint blockade the new standard of care for patients with lung cancer. However, the mechanisms contributing to the combinatorial efficacy of chemo-immunotherapy remain unknown. Therefore, drug combinations are determined based on historical regimens for lung cancer rather than scientific rationale. Our laboratory has a strong interest in understanding the mechanisms underlying treatment responses as a means of discovering new cancer treatments. The proposal described here builds on our previous work, which identified a combination of targeted therapies that potently induces cellular senescence. In addition to demonstrating durable growth arrest, these senescent cells secrete an array of cytokines that facilitate immune surveillance and tumor cell clearance. Interestingly, our preliminary data suggest that a similar senescent state can be induced by the standard chemotherapy for lung cancer. We hypothesize that this senescence may contribute to the clinically observed combinatorial efficacy between chemotherapy and T cell checkpoint blockade. We propose to characterize chemotherapy-induced senescence, with a particular emphasis on secreted immunomodulatory cytokines. We will leverage orthogonal in vitro and in vivo systems to explore the relevance of senescence to adaptive immunosurveillance, with the goal of determining whether senescence indeed contributes to cytotoxicity in the context of T cell checkpoint inhibition. In addition, we will interrogate tumor specimens from patients treated with chemotherapy, immune checkpoint blockade, or the combination to document the relevance of chemotherapy-induced senescence in patients with NSCLC. The data generated by this proposal will have direct relevance to the current state of NSCLC treatment, and they will facilitate the development of additional, potentially novel, drug combinations. These studies will be led by Dr. Matthew Bott, a junior faculty member on the thoracic surgical service at Memorial Sloan Kettering Cancer Center (MSK) with an interest in lung cancer and immunotherapy. The research will be carried out under the combined mentorship of Dr. Scott Lowe, an international leader in cancer biology, and Dr. Jedd Wolchok, a highly accomplished expert in translational immuno-oncology. MSK offers an outstanding environment for a career in basic and translational research. To achieve his goal of becoming an independent researcher, Dr. Bott has developed a structured curriculum of activities aimed at broadening his knowledge base, expanding his technical skills, and sharpening his methods for scientific inquiry.